The population of people living with HIV (PLWH) in the US are aging; it is projected that by 2015 more than half of US PLWH will be over age 50. Heart, lung, and blood diseases are common among aging PLWH, likely due to a complex interplay of HIV infection itself and resulting inflammation, antiretroviral treatments and their toxicities, viral co-infections, other co-morbid conditions, traditional risk factors such as tobaco, and other behaviors such as substance use. We propose to rigorously assess risk factors associated with increased prevalence and incidence of myocardial infarction (MI), chronic obstructive pulmonary disease (COPD), venous thromboembolism (VTE), and chronic anemia among PLWH, and to determine risk factors associated with poor outcomes from these conditions. Understanding the contribution of multiple factors to the increased risk of disease is crucial to developing strategies to improve prevention, diagnosis, and treatment of these major heart, lung and blood diseases in PLWH. This application leverages comprehensive clinical data and biorepository samples from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS), a data source specifically suggested in the RFA. This large, diverse, well-characterized multi-site cohort captures longitudinal clinical data, patient reported outcomes such as physical activity and substance use, and biospecimens facilitating a nuanced and detailed approach to addressing risk. In addition, CNICS infrastructure allows outcomes to be carefully reviewed and validated capturing key distinctions such as MI type (STEMI vs. non-STEMI) and DVT location. Our multidisciplinary team is uniquely poised to leverage these resources to address important gaps in understanding the pathophysiology, diagnosis, treatment, and impact of MI, COPD, VTE and anemia in PLWH by pursuing 3 aims. Aim 1 is to determine the prevalence and incidence of MI, COPD, VTE and anemia in PLWH, as well as their traditional and HIV-specific risk factors. Aim 2 is to determine risk factors for complicatios and poor outcomes from these four conditions in PLWH. Specific outcomes will include mortality, multi-morbidity, health-related quality of life, frailty, and polypharmacy. Aim 3 is to determine immunologic predictors of MI, COPD, VTE and anemia among PLWH, focusing on soluble markers of inflammation, coagulation, monocyte activation, and gut epithelial integrity. These investigations can identify novel targets for therapeutic interventions. New knowledge gained from these investigations will inform clinical decision making and will dramatically improve understanding of the mechanisms of heart, lung, and blood diseases in PLWH, which in turn will enhance the development of rational and targeted therapeutic approaches to improve outcomes.